Novel 2-halogenated derivatives of 5-0-desosaminyl-erythronolide A and their use.
It is an object of the invention to provide the novel compounds of formula I and their acid addition salts and a process for their preparation.
It is another object of the invention to provide novel antibiotic compositions and a method of treating bacterial infections in warm-blooded animals.
These and other objects and advantages of the invention will become obvious from the following detailed description.
The novel products of the invention are compounds selected from the group consisting of a compound of the formula 
wherein A is nitrogen or Nxe2x86x92O, R1 and R2 are individually selected from the group consisting of hydrogen and alkyl of 1 to 18 carbon atoms, R is selected from the group consisting of hydrogen and xe2x80x94(CH2)mOB, Hal is halogen, m and n are individually an integer from 1 to 8, B is hydrogen or 
Ar is a mono- or polycyclic aryl or heteroaryl, Z is hydrogen or acyl of an organic carboxylic acid of up to 18 carbon atoms and its non-toxic, pharmaceutically acceptable acid addition salts.
Examples of acids for the acid addition salts are acetic acid, propionic acid, trifluoroacetic acid, maleic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and particularly stearic acid, ethylsuccinic acid or laurylsulfonic acid.
Examples of alkyl are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl and dodecyl.
Examples of aryl are phenyl or naphthyl and examples of heteroaryl are thienyl, furyl, pyrolyl, thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, pyrazolyl or isopyrazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl and also indolyl, benzofurannyl, benzothiazyl and quinolinyl.
Examples of substituents are at least one of hydroxyl, halogen, xe2x80x94NO2, xe2x80x94Cxe2x89xa1N, alkyl, alkenyl or alkynyl, O-alkyl, O-alkenyl or O-alkynyl, S-alkyl, S-alkenyl or S-alkynyl and N-alkyl, N-alkenyl or N-alkynyl of up to 12 carbon atoms optionally substituted by at least one halogen, 
Ra and Rb individually being hydrogen or alkyl of up to 12 carbon atoms, 
R3 being alkyl of up to 12 carbon atoms, or an optionally substituted aryl or heteroaryl radical, carbocyclic aryl, O-aryl or S-aryl, or heterocyclic aryl, O-aryl or S-aryl with 5 or 6 members comprising at least one heteroatom, optionally substituted by one or more of the above substituents.
Hal is halogen, preferably fluorine or chlorine. When one of the substituents is halogen, it is preferably fluorine, chlorine or bromine.
Among the preferred compounds of formula I are those wherein R1 and R2 are hydrogen, those wherein A is nitrogen, those wherein Hal is fluorine, those wherein R is hydrogen and those wherein R is xe2x80x94CH2OH.
The process for the preparation of a compound of formula I comprises reacting a compound of the formula 
wherein Hal is halogen and OM is a protected hydroxyl with a compound of the formula 
wherein m is an integer from 1 to 8 to obtain a compound of the formula 
deprotecting the 2xe2x80x2-hydroxyl to obtain a compound of the formula 
reacting the latter with a debenzylating agent to obtain a compound of the formula 
reacting the latter with a cyclization agent to form a compound of the formula 
wherein R is xe2x80x94(CH2)mxe2x80x94OH and optionally subjecting the latter to aralkylating or acylating agent to obtain a compound of claim 1 wherein B is xe2x80x94(CH2)nxe2x80x94Ar or 
The starting compounds of formula II are described in French patent application 98-04366 filed Apr. 8, 1998 and a detailed description of the process for the preparation of compounds of formula II wherein Hal is fluorine is described herein.
The process comprises reacting a compound of the formula 
wherein xe2x80x94OZ is xe2x80x94OH or a protected hydroxyl with a fluorination agent to obtain a compound of the formula 
which is then reacted with carboxyldiimidazole to obtain the compound of formula II. Other products can be prepared in an analogous manner.
Preferably, OZ is acetyl or benzoyl and the protected hydroxyl can be released by methanolysis. The debenzylation may be effected by hydrogenation such as with palladium on carbon in the presence of ammonium formate at methanol ref lux and cyclization may be effected at ethanol ref lux in the presence of acetic acid. The acylation or arylation can be carried out by standard procedures.
The compound S of formulae IV, V and VI are novel and are part of the invention.
In a variation of the process to prepare the compounds of formula I, a compound of the formula 
wherein A, R, R1 and R2 are defined as above and xe2x80x94OM is a protected hydroxyl is reacted with a halogenation agent to obtain a compound of the formula 
which is optionally reacted with an agent to free the 2xe2x80x2-hydroxyl to obtain the compound of formula I wherein in Z is hydrogen and optionally with an esterification agent to obtain the 2xe2x80x2-acylated compound or with an acid to form the acid addition salt.
The preferred halogenation agent is bisphenyl sulfonylimide of the Formula 
The novel antibiotic compositions of the invention are comprised of an antibiotically effective amount of a compound of formula I and its non-toxic, pharmaceutically acceptable acid addition salts and an inert pharmaceutical carrier. The compositions may be in the form of plain or sugar-coated tablets, gelatin capsules, granules, suppositories, injectable preparations, ointments, creams, gels.
Examples of the pharmaceutical carriers are talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives.
The compositions can also be present in the form of a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example, apyrogenic sterile water.
The compositions have a very good antibiotic activity on gram ⊕ bacteria such as staphylococcis, streptococcis, pneumococcis and therefore are useful in the treatment of germ-sensitive infections and particularly in that of staphylococcia such as staphylococcal septicaemias, malignant staphylococcia of the face or skin, pyodermitis, septic or suppurant wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as primitive or post-influenzal acute angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute angina, otitis, sinusitis, scarlatina, pneumococcia such as pneumonia, bronchitis; brucellosis, diphtheria, gonococcal infection.
The compositions are also active against infections caused by germs such as Haemophilus influenzae, Rickettsia, Mycoplasma pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma, or germs of the Mycobacterium genus.
The method of treating bacterial infections in warm-blooded animals comprises administering to a warm-blooded animal an antibiotically effective amount of a compound of formula I or its acid addition salt. The compounds can be administered buccally, rectally, parenterally or by topical application on the skin and mucous membranes, but the preferred administration route is the buccal route. The usual effective daily dose is 2 to 15 mg/kg depending on the method of administration and the active compound.